Process for producing delta 8, 9-7-keto-11-hydroxy steroids



United States Patent PROCESS FOR PRDDUCING A -7-KETO-11- HYDROXYSTEROIDS Leopold Rnzicka, Hans Heusser, and Oskar Jeger, Zurich,Switzerland, assignors to Ciba Pharmaceutical Products, Inc., Summit, N.J.

No Drawing. Application December 13, 1951, Serial No. 261,582

Claims priority, application Switzerland December 22, 1950 5 Claims.(Cl. 260--397.1)

The present invention is concerned with a new process leading to newcompounds which make it possible to synthesize therapeutically activesteroids containing oxygen in the ll-position.

The steroids with oxygen in ll-position are of great importance. Animportant representative of this class of compounds is for examplecortisone, A -3,11,20-trioxo- 17a,2l-dihydroxy-pregnene. The hithertoknown processes for the synthetic production of such steroids use asstarting materials desoxycholic acid and its derivatives, that is to saycompounds which possess a hydroxyl group in 12-position. It has beenshown however that the transfer of oxygen from the 12- to thell-position is a very tedious process requiring several operations. Inaddition the desoxycholic acid used as starting material is onlyobtainable in relatively limited quantity, so that for example it ispractically impossible to manufacture the cortisone required in therapyin sufficient quantity by this method. A requirement therefore existsfor new sources for the manufacture of this medicament. The easilyavailable sterols, such as ergosterol, stigmasterol or sitosterol, butmore especially cholesterol, have indeed for many years been importantstarting materials for the production of sex hormones. They have howeverhitherto been without importance for the production of compounds withoxygen in the ll-position of the intact steroid structure.

The present invention is based on the observation that by starting fromthe above-mentioned sterols or conversion products thereof, compounds ofthe steroid series with oxygen in the 1l-position can be obtained, whena M -steroid is treated with an agent capable of introducing oxygen, theresultant A' -9,11-oxido compound is isomerized, an oxidizing agent iscaused to act on the A -7,1l-dihydroxy-compound formed, the resultant A-7-oxo-1l-hydroxy-steroid is treated with a hydrogenating agent and theoxo-group in 7-position is removed by reduction.

The process is illustrated by the following diagram of partial formulae:

-An object of the present invention are A -7-oxo-l1- hydroxy-steroids.These compounds are new and are intended for use as intermediateproducts for the preparation of ll-oxo-steroids and ll-hydroxy-steroids.Thus, e. g., the present invention is a step in the preparation of3aacetoxy-1l-oxo-cholanate (see c. g. Example 5 of copending applicationS. N. 261,581, filed on even date herewith) which is a recognized andwell known intermediate for the production of the highly active hormone1l-dehydro-corticosterone (cf. Wettstein & Meystre: Helv. Chim. Acta,vol. 30, p. 12614265 (1947)). Another object of the invention is aprocess for the manufacture of A -7-oxo1l-hydroXy-steroid. It comprisestreating a A -7,1l-dihydroxy-steroid with a member selected from thegroup of tertiary butylchromate and bromosuccinimide.

These A -7,1l-dihydroxy-steroids belong to thecyclepentanopolyhydrophenanthrene or the polyhydrochrysene series.Particular importance is attached to the derivatives of cholestane,coprostane, sitostane, stigmastane, cholane, allocholane, pregnane,androstane and etiocholane. In addition to the aforementioned doublebond, the starting materials may have other double bonds. They can beobtained, e. g. according to copending U. S. patent application SerialNo. 261,578, filed December 13, 1951, by isomerizing A-9,11-oxido-steroids with acids under mild conditions.

For the oxidation according to the invention, tertiary butylchromate orbromosuccinimide are used in the presence of a diluent, such as anorganic solvent, e. g. a halogenated hydrocarbon, especially carbontetrachloride.

The following examples illustrate the invention, the relation betweenparts by weight and parts by volume being the same as that between thegram and the cubic centimeter:

Example 1 0.22 part by weight of crude A -7,11-dihydroxy-3,3,17,8-diacetoxy-androstene of melting point 208-210 C. (preparedaccording to U. S. patent application Serial No. 261,578, filed December13, 1951) is dissolved in 2.5 parts by volume of carbon tetrachloride.0.5 part by volume of a solution of tertiary butyl chromate, which hadbeen prepared from 0.093 part by weight of chromium trioxide and freedfrom excess tertiary butanol, is added to the above solution whilecooling with ice and stirring. The stirring is continued at 0 C. forhalf an hour and then at room temperature for 4 /2 hours. The excess ofthe oxidizing agent is destroyed by addition of 1 part by weight ofoxalic acid dissolved in 10 parts by volume of water and 2 parts byvolume of 2-n sulfuric acid. The reaction mixture is diluted with 60parts by volume of ether, the organic layer washed with Water,bicarbonate and water, dried and evaporated. 0.233 part by weight of alight yellow residue is obtained, which is dissolved in methanol and thesolution is concentrated to a small volume. On cooling the M -313,176-diacetoxy-7-oxo-1l-hydroxy-androstene, of melting point 190.5192 C.separates in nice crystals. It shows in the ultraviolet spectrum anabsorption maximum at 248 mu (log 5:3.9).

Example 2 1 part by volume of powdered A -3;3-acetoxy-7,1l-dihydroxy-ergostadiene of melting point 269-270 C. (preparedaccording to U. S. patent application Serial No. 261,578, filed December13, 1951) is suspended in parts by volume of carbon tetrachloride andtreated with 30 parts by volume of a solution of tertiary butyl chromatein carbon tetrachloride (corresponding to 0.035 part by weight ofchromic acid per part by volume). The reaction mixture is kept at 10 C.for 8 hours, then 4 parts by volume of oxalic acid dissolved in waterand 10 3. parts by volume of 2 N-sulfuric acid are added. The reactionmixture is vigorously stirred for 1 hours, diluted with 200 parts byvolume of chloroform, the organic layer separated and washedconsecutively with water, sodium bicarbonate solution and water, driedand evaporated in vacuo. The crude product is chromatographed overalumina, whereby 0.5 part by weight of ABYQiZZ'ZK 3/3 acetoxy7-oxo-1l-hydroxy-ergostadiene is obtained, which can be recrystallizedfrom a mixture of methanol and water and melts at 235 C. In theultraviolet absorption spectrum it shows a maximum at 252 my (loge=3.98).

Example 3 1 part by weight of finely powdered A 33-acetoxy-7,l1dihydroxyergostadiene (prepared according to U. S. patentapplication Serial No. 261,578, filed December 13, 1951) is dissolved ina mixture of 200 parts by volume of dioxane and 40 parts by volume ofwater and 50 parts by weight of N-bromosuccinimide are added. Thereaction mixture is kept at 20 C. for 20 hours, diluted with 400 partsby volume of water and extracted with 400 parts by volume of ether. Theorganic layer is separated and washed with water, sodium bicarbonate andwater, dried and evaporated. The crude reaction product ischromatographed over alumina and from the crystalline fractionsAli-$2233 3B acetoxy-7-oxo-11-hy- 'roxy-ergostadiene of melting point235 C. is obtained.

Example 4 0.5 part by weight of finely powdered A -3B-acetoxy-7,1l-dihydroxy-cholestene of melting point 228-230" C. (preparedaccording to U. S. patent application Serial No. 261,578, filed December13, 1951) is suspended in 60 parts by volume of carbon tetrachloride,cooled to C., and 5 parts by volume of a solution of tertiary butylchromate in carbon tetrachloride (corresponding to 0.93 part by weightof chromic acid) slowly dropped in within minutes while stirring. Thereaction mixture immediately turns dark when the oxidizing agent isadded and the starting material dissolves completely. The reactionmixture is stirred for 5 hours at 0 C. The excess butyl chromate isdestroyed with 5 parts by weight of oxalic acid dissolved in Water andthe reaction worked up as described in Example 1. 0.48 part by weight ofa slightly yellow oil is obtained, which is chromatographed overaluminum oxide. By this method the crystalline A-3p-acetoxy-7-oxo-1l-hydroxy-cholestene is obtained, which can berecrystallized from ethanol or from a mixture of acetone and water. Itexhibits strong absorption in the ultraviolet absorption spectrum at 250m (log e=3.96) and shows in the infra-red spectrum a sharp band at 3402cm.- typical for a free hydroxyl group in addition to the strong bandsof the acetate and ,fi-UD- saturated oxo group at 1730 cm? and 1660 cmfrespectively.

Example 5 1.2 parts by weight of the oily methyl A -3a-acetoxy-7,11-dihydroxy-cholenate (prepared according to U. S. patent applicationSerial No. 261,578, filed December 13, 1951) are dissolved in a mixtureof 200 parts by volume of pure dioxane and 50 parts by volume of water.To the clear and well stirred solution 60 parts by weight ofN-bromo-succinimide are added. The reaction mixture is kept at roomtemperature for 18 hours. 450 parts by volume of water are then addedand the solution extracted with 800 parts by volume of ether in 3portions. The combined ethereal solutions are washed with water, sodiumbicarbonate and again with water, dried with magnesium sulfate andevaporated. The crude reaction product is chromatographed over aluminaand from the crystalline fractions methyl A-3u-acetoxy-7-oxo-11-hydroxy-cholenate is obtained. The product shows inethanol solution an ultraviolet absorption maximum at 249 m (log e=3.9).

By using A -3B,17,8-diacetoxy-7,1l-dihydroxy-androstene, A-3/3-acetoxy-7,1l-dihydroxy-cholestene, A -3B-20-diacetoxy-7,11-dihydroxy-allo-pregnene or A -3/8-acetoxy-7,1l-dihydroxystigmastadiene as starting materials and bytreating them with N-bromosuccinimide in an analogous manner thecorresponding A -7-ox0-11- hydroxy-steroids can be produced.

Example 6 0.8 part by weight of crude A -3fi,20-diacetoxy-7,11-dihydroxy-allo-pregnene (prepared according to U. S. patent applicationSerial No. 261,578, tiled December 13, 1951) is suspended in parts byvolume of carbon tetrachloride and cooled to 0 C. To the well stirredreaction mixture 8 parts by volume of a solution of tertiary butylchromate in carbon tetrachloride (prepared from 0.298 part by weight ofchromic acid and freed from excess tertiary butanol by azeotropicdistillation of the alcohol with carbon tetrachloride) are graduallyadded within 15 minutes. Stirring is continued at 0 C. for 6 hours, whena solution of 10 parts by weight of oxalic acid in water is added. Thereaction mixture can be acidified further by addition of 5 parts byvolume of 2 N-sulfuric acid to dissolve any precipitate that may havebeen formed. After 2% hours the mixture is diluted with ether, theorganic layer separated, washed with water, sodium bicarbonate andwater, dried and evaporated. It is to be recommended to chromatographthe crude reaction product over aluminum oxide. From the crystallinefractions pure A -35,20-diacetoxy-7-oxo- 1l-hydroxy-allo-pregnene isobtained. In the infra-red spectrum it shows a very strong band at 1710cm. and a weaker band at 1780 cmr which are assigned to the acetatecarbonyl and rap-unsaturated carbonyl group, and in addition a fairlysharp band at 3410 cm. indicating a free hydroxyl group.

If the tertiary butyl chromate is caused to react on methyl A-3wacetoxy-7Jl-dihydroxy-cholenate in an analogous way methyl A-3a-acetoxy-7-oxo-1l-hydroxycholenate is obtained.

What is claimed is:

l. A process for the conversion of a member selected from the groupconsisting of A -3-1ower alkylcarbonyloxy-7,1l-dihydroxy-androstenes, A-3-lower alkylcarb0nyloxy-7,11-dihydroxyergostadienes, A -3-lowerall;ylcarbonyloxy-7,11 dihydroxy-cholestenes, A -3-loweralkylcarbonyloxy 7,11 dihydroxy-cholenes, A -loweralkylcarbonyloxy-7,11-dihydroxy-allopregnenes and A 3 loweralkylcarbonyloxy-7,11-dihydroxystigmastadienes into the corresponding7-oxo 11 hydroxy-compound, which comprises treating the said member ofthe said group with a member selected from the group consisting oftertiary butyl chromate and N-bromosuccinimide.

2. A process for the conversion of a lower alkyl A -3-loWeralkylcarbonyloxy-7,1l dihydroxy-cholenate to the corresponding loweralkyl A -3-lower alkylcarbonyloxy-7-oxo 11 hydroxy-cholenate, whichcomprises treating the lower alkyl A 3 lower alkylcarbonyloxy 7,11dihydroxy-cholenate with N-bromosuccinimide.

3. A process for the conversion of a lower alkyl A -3- acetoxy-7,11dihydroxy-cholenate to the corresponding lower alkyl A -3-acetoxy7-0xo-1l-hydroxy-cholenate, which comprises treating the lower alkyl A-3-acetoxy- 7,11 dihydroxy-cholenate with tertiary butyl chromate incarbon tetrachloride solution.

4. A process for the conversion of methyl A -3aacetoxy 7,11dihydroxy-cholenate to the corresponding methyl A -3a-acetoxy-7-oxoll-hydroxy-cholenate, which comprises treating the methyl A -3u-acetoxy-7,11-dihydroxy-cholenate with N-bromosuccinimide.

5. A process for the conversion of methyl A 31-acetoxy-7,1l-dihydroxy-cholenate to the corresponding methyl A-3oc-&CtOXy 7 oxo 11 hydroxy-cholenate,

5 which comprises treating the methyl A -3wacetoxy-7,11-dihydroxy-cholenate with tertiary butyl chromate in carbontetrachloride solution.

References Cited in the file of this patent UNITED STATES PATENTS2,569,300 Fieser et al. Sept. 25, 1951 6 OTHER REFERENCES Fieser et al.:Natural Products Related to Phenanthrene, 3rd ad, page 425 (1949).

1. A PROCESS FOR THE CONVERSION OF A MEMBER SELECTED FROM THE GROUPCONSISTING OF $8,9-3-LOWER ALKYLCARBONYLOXY-7,11-DIHYDROXY-ANDROSTENES,$8,9-3-LOWER ALKYLCARBONYLOXY-7,11-DIHYDROXYERGOSTADIENES, $8,9-3-LOWERALKYLCARBONYLOXY-7,11 - DIHYDROXY-CHLESTENES, $8,9-3-LOWERALKYLCARBONYLOXY - 7,11 - DIHYDROXY-CHOLENES, $8,9-LOWERALKYLCARBONYLOXY-7,-11-DIHDROXY-ALLOPREGNES AND $8,93 - LOWERALKYLCARBONYLOXY-7,11-DIHYDROXYSTIGMASTADIENES INTO THE CORRESPONDING7-OXO- - 11 - HYDROXY-COMPOUND, WHICH COMPRISES TREATING THE SAID MEMBEROF THE SAID GROP WITH A MEMBER SELECTED FROM THE GROUP CONSISTING OFTERLIARY BUTYL CHROMATE AND N-BROMOSUCCINIMIDE.